Ligand-enabled distal desaturative lactonization of aliphatic acids

Transition metal catalysis serves as a fundamental strategy for transforming inert C−H bonds into valuable functional motifs. 1,2 However, achieving regioselective activation of remote C−H bonds remains challenging, particularly in unbiased hydrocarbon frameworks. 2,3 In this context, distal C(sp 3 )−H bonds are especially difficult to functionalize, as conformational flexibility favors proximal C−H activation. 3,4 In this study, we demonstrate a ligand-enabled strategy using designed O -allyl amido ester (OAAE) ligands for palladium-catalyzed activation of γ-methylene and methine C−H sites in unbiased aliphatic carboxylic acids, derived from readily available fatty and cyclic acid feedstocks. This protocol enables direct transformation of aliphatic carboxylic acid substrates into distal desaturated γ-lactones and double dehydrogenated γ-spirolactones. Mechanistic studies are consistent with a pathway involving Pd(II)-mediated γ-C(sp 3 )−H activation, followed by dehydrogenation and intramolecular cyclization. These lactones with an unsaturated arm, serve as key intermediates for the formation of complex natural products and pharmaceuticals. For instance, muricatacin (from soursop/ laxman phal ) and its analogue were rapidly assembled in three steps from margaric acid using this strategy and evaluated for anticancer activity, thereby demonstrating the potential of our approach for providing a rapid access to biologically relevant frameworks for traditional medicine. …